Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic.

The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases.

First trimester screening using ultrasound and serum markers in Panamanians: Factors associated with adverse pregnancy outcomes.

BACKGROUND: There is no published data on the association between serum biochemical and ultrasonographic markers and adverse pregnancy outcomes. Therefore, the aim of this study was to determine the factors associated with perinatal outcomes in singleton pregnancies using ultrasound and maternal serum markers during the first trimester in Panamanians. MATERIALS AND METHODS: This was a prospective observational study of 468 first trimester singleton pregnancies conducted over a 7-year period. All women attending a prenatal screening clinic during the study period were informed of the study and the option to participate. Two maternal serum markers, free ß-human chorionic gonadotropin (ß-hCG) and pregnancy associated plasma protein-A (PAPP-A), and four fetal ultrasound markers, nuchal translucency thickness, nasal bone, flow across the tricuspid valve, and flow in the ductus venosus (DV), were measured by certified maternal fetal medicine specialists. Adverse outcomes included miscarriage, major structural defects, genetic disorders, and major fetal cardiac defects. RESULTS: A total of 454 (97%) pregnancies were unaffected. Median maternal age was 31.5 years (range: 18-50). Maternal age was significantly greater in cases of adverse outcome (P = 0.007). The number of adverse outcomes associated with an absent or hypoplastic nasal bone, tricuspid valve regurgitation, and abnormal flow in the DV were significantly greater relative to unaffected pregnancies (Ps < 0.001). No differences were found in fetal crown-rump length or maternal serum levels of ß-hCG or PAPP-A. CONCLUSION: Abnormal ultrasound markers are associated with adverse outcomes. Women with normal ultrasound and serum markers should be reassured of low risk of adverse pregnancy outcomes.

Lethality associated with snake venom exposure can be predicted by temperature drop in Swiss mice.

Establishing humane endpoints to minimize animal suffering in studies on snake venom toxicity and antivenom potency tests is crucial. Our findings reveal that Swiss mice exhibit early temperature drop following exposure to different snake venoms and combinations of venoms and antivenoms, predicting later mortality. Evaluating temperature we can identify within 3 h post-inoculation, the animals that will not survive in a period of 48 h. Implementing temperature as a criterion would significantly reduce animal suffering in these studies without compromising the outcomes.

Correction: De Jesus et al. Body Temperature Drop as a Humane Endpoint in Snake Venom-Lethality Neutralization Tests. Toxins 2023, 15, 525.

In the original publication [...].

Predictors of cognitive change in cognitively healthy older women in Panama: the PARI-HD study.

Background: Evidence suggests that a combination of biological and social factors influence risk of dementia differently for women and men. In healthy older women, several factors may contribute to changes in cognition. Objective: Describe the characteristics associated with variation in cognition in a sample of cognitively healthy older Panamanian women. Methods: The study includes cross-sectional analyses of cognitive domains at baseline (n = 357) and 17-month (SD = 2.0) follow-up (n = 200) for women aged 60 years and older enrolled in the Panama Aging Research Initiative-Health Disparities (PARI-HD) study. Instruments included clinical questionnaires, physiological measures, and a neuropsychological test battery assessing global cognition and seven cognitive domains. Multiple regression analyses examined the associations between demographic and clinical characteristics and cognition at baseline. Repeated measures analyses were used to investigate changes in cognition from baseline to follow-up. Results: On average, participants were 68.6 years of age (SD = 5.9) with 16.1 years of education (SD = 4.7). Age, income, and education showed robust associations with baseline cognition. Subjective cognitive impairment was associated with lower performance in global cognition, verbal learning, and memory domains. Only performance in the attention domain decreased at follow-up, and subjective health state and depressive symptoms significantly predicted the change in attention. Discussion: Our study findings contribute to the investigation of cognitive health in older Hispanic women and to the understanding of sociodemographic and health-related factors associated with cognitive decline and the progression to cognitive impairment and dementia.

Polypharmacy and Associated Health Outcomes in the PARI-HD Study.

Background: A growing body of evidence points to potential risks associated with polypharmacy (using ≥5 medications) in older adults, but most evidence is derived from studies where racial and ethnic minorities remain underrepresented among research participants. Objective: Investigate the association between polypharmacy and cognitive function, subjective health state, frailty, and falls in Hispanic older adults. Methods: Panama Aging Research Initiative-Health Disparities (PARI-HD) is a community-based cohort study of older adults free of dementia at baseline. Cognitive function was measured with a neuropsychological test battery. Frailty assessment was based on the Fried criteria. Subjective health state and falls were self-reported. Linear and multinomial logistic regression analyses were used to examine association. Results: Baseline evaluations of 468 individuals with a mean age of 69.9 years (SD = 6.8) were included. The median number of medications was 2 (IQR: 1-4); the rate of polypharmacy was 19.7% (95% confidence interval [CI] = 16.1-23.3). Polypharmacy was inversely associated with self-rated overall health (b =-5.89, p < 0.01). Polypharmacy users had 2.3 times higher odds of reporting two or more falls in the previous 12 months (odds ratio [OR] = 2.31, 95% CI = 1.06-5.04). Polypharmacy was independently associated with Fried's criteria for pre-frailty (OR = 2.90, 95% CI = 1.36-5.96) and frailty (OR = 5.14, 95% CI = 1.83-14.42). Polypharmacy was not associated with cognitive impairment. Conclusions: These findings illustrate the potential risks associated with polypharmacy among older adults in Panama and may inform interventions to improve health outcomes in this population.

Resilience mediates the effect of the COVID-19 pandemic on mental health in a sample of adults in Panama.

Background: The COVID-19 pandemic was characterized by global increases in depression, anxiety, and stress symptoms. Previous studies have shown that resilience mitigates these symptoms, however there is limited research exploring the link between resilience and mental illness during the COVID-19 pandemic in Central America. Objective: To examine the role of resilience as it relates to the perceived effect of the pandemic on mental health symptoms. Methods: A sample of 480 adults in Panama were recruited from March to May 2021 to complete an online survey. The online survey consisted of sociodemographic questions and scale measures assessing depression, anxiety and stress symptoms, resilience, and social support. Results: Results indicated that resilience mediated the relationship between the perceived effect of the COVID-19 pandemic and mental health symptoms; participants who felt more personally affected by the pandemic reported more depression, anxiety, and stress symptoms via decreased resilience. Further analyses revealed that resilience was moderated by sex and social support, showing that the indirect effect of resilience was greater for women and individuals who perceived low social support. Discussion: These findings contribute to a growing body of research documenting the adverse effects of the COVID-19 pandemic on mental health and reveal potential mechanisms through which pandemic-related distress decreases resilience, thereby increasing symptoms of mental illness.

Body Temperature Drop as a Humane Endpoint in Snake Venom-Lethality Neutralization Tests.

Snake venom neutralization potency tests are required for quality control assessment by manufacturers and regulatory authorities. These assays require the use of large numbers of mice that manifest severe signs associated with pain and distress and long periods of suffering. Despite this, many animals make a full recovery; therefore, the observation of clinical signs as a predictor of animal death is highly subjective and could affect the accuracy of the results. The use of a more objective parameter such as body temperature measurement could help establish a humane endpoint that would contribute to significantly reducing the suffering of large numbers of animals. We determined the temperature drop in BALB/c mice exposed to the mixtures of Bothrops asper or Lachesis stenophrys venom and a polyvalent antivenom by using an infrared thermometer. Our data show that, based on the temperature change from baseline, it is possible to predict which animals will survive during the first 3 h after inoculation. The data provided in this study may contribute to future reductions in animal suffering, in concordance with general trends in the use of laboratory animals for the quality control of biologicals.

Digital phenotyping: An equal opportunity approach to reducing disparities in Alzheimer's disease and related dementia research.

A rapidly aging world population is fueling a concomitant increase in Alzheimer's disease (AD) and related dementias (ADRD). Scientific inquiry, however, has largely focused on White populations in Australia, the European Union, and North America. As such, there is an incomplete understanding of AD in other populations. In this perspective, we describe research efforts and challenges of cohort studies from three regions of the world: Central America, East Africa, and East Asia. These cohorts are engaging with the Davos Alzheimer's Collaborative (DAC), a global partnership that brings together cohorts from around the world to advance understanding of AD. Each cohort is poised to leverage the widespread use of mobile devices to integrate digital phenotyping into current methodologies and mitigate the lack of representativeness in AD research of racial and ethnic minorities across the globe. In addition to methods that these three cohorts are already using, DAC has developed a digital phenotyping protocol that can collect ADRD-related data remotely via smartphone and/or in clinic via a tablet to generate a common data elements digital dataset that can be harmonized with additional clinical and molecular data being collected at each cohort site and when combined across cohorts and made accessible can provide a global data resource that is more racially/ethnically represented of the world population.

Cognitive and emotional behavioural changes associated with methylphenidate treatment: a review of preclinical studies.

There is evidence from animal studies that repeated exposure to methylphenidate (MPH), a widely used psychostimulant for the treatment of attention deficit hyperactivity disorder (ADHD), produces behavioural, structural and neurochemical changes that persist long after drug administration has ended. However, the translational utility of much of this work is compromised by the use of drug doses and routes of administration that produce plasma and brain MPH levels that fall outside the clinical range, i.e. experimental parameters more relevant to drug abuse than ADHD. We used PubMed to identify pre-clinical studies that employed repeated MPH administration at low doses in young rodents and examined long-term effects on cognition, emotion, and brain structure and function. A review of this work suggests that repeated MPH treatment during early development can modify a number of cognitive, behavioural and brain processes, but these are reduced when low therapeutic doses are employed. Moreover, MPH sites of action extend beyond those implicated in ADHD. Studies that combined neurobiological and behavioural approaches provide important insights into the mechanisms underlying MPH-produced effects on cognitive and behavioural processes, which may be relevant to MPH therapeutic efficacy. There is an emerging consensus that pharmacological treatment of childhood psychiatric disorders produces persistent neuroadaptations, highlighting the need for studies that assess long-term effects of early developmental pharmacotherapy. In this regard, studies that mimic clinical therapy with rodents are useful experimental approaches for defining the behavioural and neural plasticity associated with stimulant therapy in paediatric populations.

Psychosocial response to the COVID-19 pandemic in Panama.

Background: The impact of the COVID-19 pandemic and the associated restrictions on mental health is being studied. Objective: To analyze the psychosocial response to the COVID-19 pandemic in adults residing in Panama. Methods: A community sample of 480 adult residents of Panama completed a survey that included sociodemographic questions, COVID-19 related questions (e.g., health concerns regarding the virus, knowledge and behaviors in biosafety) and scales of stress, anxiety, depression, prosocial behavior, resilience, perceived social support, and insomnia. Results: Most of the participants (>60%) reported being negatively affected by the pandemic. Women experienced greater depression, anxiety, and stress symptoms than men, and age was negatively associated with depression, anxiety, and stress symptoms. Self-perceived health status and self-perceived social support were negatively associated with depression, anxiety, and stress symptoms. Self-perceived social isolation was positively associated with depression, anxiety, and stress symptoms. Psychiatric illness and insomnia were positively associated with depression, anxiety, and stress symptoms, whereas psychological resilience was negatively associated with depression, anxiety, and stress symptoms. Discussion: These results corroborate other studies regarding COVID-19 and mental health. This study highlights the need for specific prevention and intervention mechanisms related to the COVID-19 pandemic in different population groups. This is the first report of the psychological impact of COVID-19 in the general Panamanian population and one of the only studies in the Latin American region and, therefore, contributes to research in the Latino population and lower-middle income countries.

Estimated prevalence of attention-deficit/hyperactivity disorder in a sample of Panamanian school-aged children.

The present study investigated the prevalence of ADHD in a school sample of children ages 6-11 years in the city of Panama. The assessment battery included the Conners' Parent and Teacher Rating Scales, the Structured Developmental History of the Behavioral Assessment System for Children (BASC-2), and the Wechsler Intelligence Scale for Children (WISC-III). The prevalence of ADHD (N = 229) was 7.4%, with an estimate of 1.8% for the predominantly inattentive subtype, 3.1% for the predominantly hyperactive/impulsive subtype, and 2.6% for the combined subtype. The prevalence rate of ADHD is relatively low in Panama compared to those reported for samples in neighboring countries. Moreover, ADHD children were unlikely to have been identified or referred to psychological or special education assessments. Our findings confirm that ADHD is overlooked in some cultures and that a significant number of children with ADHD-related impairments are not receiving optimal intervention.

Critical Review of the Alzheimer's Disease Non-Transgenic Models: Can They Contribute to Disease Treatment?

Alzheimer's disease (AD) is a growing neurodegenerative disease without effective treatments or therapies. Despite the use of different approaches and an extensive variety of genetic amyloid based models, therapeutic strategies remain elusive. AD is characterized by three main pathological hallmarks that include amyloid-ß plaques, neurofibrillary tangles, and neuroinflammatory processes; however, many other pathological mechanisms have been described in the literature. Nonetheless, the study of the disease and the screening of potential therapies is heavily weighted toward the study of amyloid-ß transgenic models. Non-transgenic models may aid in the study of complex pathological states and provide a suitable complementary alternative to evaluating therapeutic biomedical and intervention strategies. In this review, we evaluate the literature on non-transgenic alternatives, focusing on the use of these models for testing therapeutic strategies, and assess their contribution to understanding AD. This review aims to underscore the need for a shift in preclinical research on intervention strategies for AD from amyloid-based to alternative, complementary non-amyloid approaches.

Depression Mediates the Association Between Occupational Complexity and Late-Life Cognition in Hispanics.

There is a dearth of research in Latin America regarding risk and protective factors affecting older adults' cognition. This study aimed to investigate the factors mediating the association between occupational complexity and late-life cognition and daily function in a sample of Hispanic older adults. Participants (n = 588) aged 65 years and older underwent clinical, functional, and cognitive assessments. Mediation analyses revealed that depressive symptoms mediated the relationship between occupational complexity and cognitive as well as functional outcomes. Results provide evidence that depression may act as a risk factor for worse outcomes, even if older adults had a cognitively demanding occupation.

Apolipoprotein ɛ4 Affects Multiple Domains of Neuropsychological Functioning in a Sample of Elderly Hispanics.

Apolipoprotein ɛ4 allele (APOEɛ4) is the strongest genetic risk factor for sporadic Alzheimer's disease (AD), but inconsistencies have arisen in studies with Hispanics. The objective of this study was to explore APOEɛ4 expression and cognitive function in a sample of Panamanian older adults, including healthy controls, mild cognitive impairment, and AD. Participants with at least one copy of APOEɛ4 had a significantly lower performance in global cognition, verbal memory, executive functions, visuospatial abilities, regardless of diagnosis. The present study contributes to the understanding of the association of APOEɛ4 and impairment in specific cognitive domains in elderly Hispanics.

Performance of a Point of Care Test for Detecting IgM and IgG Antibodies Against SARS-CoV-2 and Seroprevalence in Blood Donors and Health Care Workers in Panama.

Novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiologic agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has reached 28 million cases worldwide in 1 year. The serological detection of antibodies against the virus will play a pivotal role in complementing molecular tests to improve diagnostic accuracy, contact tracing, vaccine efficacy testing, and seroprevalence surveillance. Here, we aimed first to evaluate a lateral flow assay's ability to identify specific IgM and IgG antibodies against SARS-CoV-2 and second, to report the seroprevalence estimates of these antibodies among health care workers and healthy volunteer blood donors in Panama. We recruited study participants between April 30th and July 7th, 2020. For the test validation and performance evaluation, we analyzed serum samples from participants with clinical symptoms and confirmed positive RT-PCR for SARS-CoV-2, and a set of pre-pandemic serum samples. We used two by two table analysis to determine the test positive and negative percentage agreement as well as the Kappa agreement value with a 95% confidence interval. Then, we used the lateral flow assay to determine seroprevalence among serum samples from COVID-19 patients, potentially exposed health care workers, and healthy volunteer donors. Our results show this assay reached a positive percent agreement of 97.2% (95% CI 84.2-100.0%) for detecting both IgM and IgG. The assay showed a Kappa of 0.898 (95%CI 0.811-0.985) and 0.918 (95% CI 0.839-0.997) for IgM and IgG, respectively. The evaluation of serum samples from hospitalized COVID-19 patients indicates a correlation between test sensitivity and the number of days since symptom onset; the highest positive percent agreement [87% (95% CI 67.0-96.3%)] was observed at ≥15 days post-symptom onset (PSO). We found an overall antibody seroprevalence of 11.6% (95% CI 8.5-15.8%) among both health care workers and healthy blood donors. Our findings suggest this lateral flow assay could contribute significantly to implementing seroprevalence testing in locations with active community transmission of SARS-CoV-2.

Intestinal volvulus in the pump twin of a twin reversed arterial perfusion (TRAP) sequence after laser therapy at 18 weeks: a case report.

BACKGROUND: Twin reversed arterial perfusion sequence is a rare and potentially lethal condition affecting approximately 1% of monochorionic twin pregnancies and 1 in 35,000 pregnancies overall. An apparently normal (pump) twin perfuses its severely malformed cotwin with deoxygenated blood via retrograde flow in direct arterioarterial anastomoses between the umbilical arteries of each twin. Fetal intestinal volvulus is a rare condition usually manifesting after birth. We report a unique case of twin reversed arterial perfusion sequence in association with intestinal volvulus in the surviving pump twin. CASE PRESENTATION: A 32-year-old Hispanic primigravida was referred to our clinic after a fetoscopy procedure of laser photocoagulation of anastomoses at 18 weeks of gestation. Follow up scans in the ex-pump twin revealed dilated bowel loops and a typical "whirlpool sign" at 26 weeks of gestation, and intrauterine intestinal volvulus was suspected. At 29 weeks of gestation, preterm premature rupture of membranes occurred, and an emergency cesarean section was performed. The newborn was diagnosed in the early neonatal period with intestinal perforation. The diagnosis was postnatally confirmed by surgery and histopathology. CONCLUSIONS: The type of fetal intervention and late gestational age of the procedure increase the risk of complications. This case alerts health providers to be vigilant in the follow-up of patients with complicated monochorionic pregnancies.

The Panama Aging Research Initiative Longitudinal Study.

The Panama Aging Research Initiative is a cohort study of 423 adults aged ≥65 years recruited from an outpatient geriatric department of Panama's largest public hospital, the Social Security Fund's Dr Arnulfo Arias Madrid Hospital Complex (Complejo Hospitalario Dr Arnulfo Arias Madrid de la Caja de Seguro Social). The study provides the first reports of modifiable and non-modifiable risk factors of cognitive impairment and dementia, as well as various health conditions common among older adults in Panama, including chronic illnesses, polypharmacy and rates of comorbidity. The initial study, conducted September 2012-May 2016, included a clinical interview; physical assessments of body mass index and handgrip strength; and cognitive testing, plus non-fasting blood draws for measurements of genetic (Apolipoprotein E genotype) and blood-based biological markers. Information was collected regarding limitations in activities of daily living, symptoms of depression and fall incidents. A subsample of participants provided cerebrospinal fluid to measure proteins related to Alzheimer's disease; another subsample underwent ultrasonography and electroencephalography. This report describes the general study design and highlights lessons learned and future directions. In particular, drawing on lessons learned from this clinical research, a community-based prospective cohort study is currently under way among older adults in Panama to validate a blood-based biomarker profile for detecting mild cognitive impairment and Alzheimer's disease, as well as risk factors for cognitive decline. KEYWORDS: Dementia, biomarkers, Latin America, aging, cognition, chronic disease, Panama.

Inflammatory Biomarkers, Depressive Symptoms and Falls Among the elderly in Panama.

BACKGROUND: Falls are common among elderly adults, and are predictors of hospitalization, institutionalization and mortality. OBJECTIVE: The objective of the present study was to examine the relationship between blood-based markers of inflammation and fall events in a sample of elderly Hispanic adults. METHOD: Data were collected from 190 participants enrolled in the Panama Aging Research Initiative study who completed baseline clinical and cognitive assessments. A non-fasting blood sample was obtained. Self-reported falls were classified as no falls, single falls or recurrent (two or more) falls reported in the 12 months prior to baseline evaluations. Serum levels of C Reactive Protein (CRP), T-lymphocyte secreting protein (I-309), interleukin 10 (IL-10), interleukin 6 (IL-6) and interleukin 7 (IL-7) were measured. Global cognition was assessed with the Mini Mental State Examination and depressive symptoms were assessed with the Geriatric Depression Scale (GDS-30). Multinomial logistic regression was used to assess the link between inflammation and fall events. RESULTS: Depressive symptoms, limitations in Instrumental Activities of Daily Living (IADL), IL-7 and I-309 were significantly related to fall events. Elevated levels of IL-7 increased the likelihood of single and recurrent falls, while increased levels of I-309 were associated only with recurrent falls. Greater IADL limitations and depressive symptoms were associated with an increased likelihood of recurrent falls. CONCLUSION: There is a lack of research investigating the relationship between inflammatory biomarkers and fall events. These results provide evidence of risk factors for falls in Hispanic older adults, and could serve to guide public health professionals to establish clinical guidelines to reduce fall risks.

Chronic sildenafil (Viagra) administration reduces anxiety in intact and castrated male rats.

Epidemiological research indicates that sildenafil (Viagra) abuse is associated with increased risk behaviors. The present study employs the open field, a standard animal model used in the field of anxiety research, to examine whether chronic exposure to sildenafil affects anxiety and risk-taking behaviors in gonadally intact and castrated male Wistar rats. Sildenafil (10 mg/kg) or saline were administered three times a week for three weeks. Animals were tested once a week in the open field during and after drug treatment. Sildenafil treatment increased the number of center entries and time spent in the center in intact and castrated animals during and after treatment, suggesting that repeated drug use decreases anxiety. Sildenafil also restored the deficits in exploration and locomotion produced by castration, indicating that sildenafil effects on open field behaviors are independent of endogenous androgens. We caution against generalizing from this study to human behaviors, but propose that the behavioral effects produced by a chronic high dose of sildenafil warrant further studies into its abuse potential.